SOX1在结直肠癌化疗耐药过程中的作用及其分子机制

Recent studies have demonstrated that cancer stem cell is a major contributor to chemoresistance, but the exact molecular mechanism is still unclear. .. We previously used genomic data from the public cancer database (The Cancer Genome Atlas) and identified the chemoresistance-related genes in colorectal cancer (CRC), in which we found that SOX1 was significantly upregulated in CRC tissues with chemoresistance, and the expression level of SOX1 was inversely correlated with the overall survival of CRC patients. In our preliminary data, we showed that ectopic expression of SOX1 activated Wnt and STAT3 signaling pathways to maintain cancer stem cell , which cause tumor resistance to the treatment of 5-Fluorouracil, Folinic-acid and Oxaliplatin in vitro and in vivo. ..In the present study, we will conduct a complementation analysis by cell functional and molecular biology studies to confirm the relationship of SOX1-induced stemness and chemoresistance in colorectal cancer. With chromosome immunoprecipitation and high-throughput sequencing, we will explore the downstream factor and signaling pathway of SOX1. In addition, we also plan to analyze the correlation between SOX1 and clinicopathologic feature, and to further determine the role of SOX1 in the patients’ prognosis. This project is valuable to further clarify the molecular mechanism of cancer chemoresistance, which may supply a new clue for the diagnosis and individual treatment.

近年来的研究表明，肿瘤干细胞的存在是结直肠癌化疗耐受的重要原因之一，其详细的分子机制尚未明了。基于大量组学数据，我们发现干细胞转录因子SOX1在耐药病人癌组织中的表达显著升高； 我们的前期实验结果显示，SOX1可提高结肠癌细胞系对化疗药物（5-氟尿嘧啶，亚叶酸和奥沙利铂）耐受性，并通过激活Wnt和STAT3信号通路来维持结直肠癌细胞的干细胞样特性。本项目将采用基因过表达、RNA干扰和细胞功能学分析等方法，确定SOX1在维持肿瘤细胞干性和增强结直肠癌细胞耐药过程中的作用；采用免疫共沉淀和基因高通量测序技术，确定SOX1调控的基因谱和信号通路；采用免疫组织化学和PCR检测技术，确定SOX1与临床病理特征和生存预后之间的相关性。该项目的实施，对于进一步阐明结直肠癌化疗耐药的分子机制具有重要的学术价值，也将为肿瘤的个体化治疗提供新的途径。

结直肠癌是消化系统常见的恶性肿瘤，在世界范围内结直肠癌的发病率排名第三位。对于中晚期结直肠癌患者来说，化疗是主要的治疗手段，但临床上大部分的患者随着病程的进展对化疗药物产生耐药性，最终导致化疗失败以及疾病复发。因此，耐药机制的阐明和生物标记物的开发为提供新治疗策略，改善患者预后至关重要。在这项研究中，基于大量组学数据，我们发现干细胞转录因子SOX1在结直肠癌化疗耐药病人癌组织中的表达显著升高并且癌患者较差的总体生存期有关。同时，高表达SOX1显著增强了结直肠癌细胞的化疗耐药性，并促进了干细胞样特性；而沉默SOX1在体外和体内都有相反的效果。机制上，过表达的SOX1激活了NF-κB通路，通过增强p65与粒细胞-巨噬细胞集落刺激因子(GM-CSF)的启动子区域结合，促进下游基因GM-CSF的表达，从而介导肿瘤干细胞表型，增强肿瘤致瘤性。我们的研究结果表明SOX1上调GM-CSF以赋予肿瘤干性特征和化疗耐药性，提示SOX1有可能成为结直肠癌化疗耐药的潜在靶标和生物标志物。